Obesity, type 2 diabetes (T2DM) and insulin resistance are independent risk factors for heart failure, which affects a rapidly increasing segment of the US population. The long-term goal of this proposal is to understand the mechanisms linking these metabolic disorders and left ventricular (LV) dysfunction prior to and in concert with heart failure. Obesity is associated with insulin resistance, hyperlipidemia, glucose intolerance and hyperinsulinemia. Epidemiological studies suggest that hyperinsulinemia is an independent risk factor for heart failure. In humans and mouse models, the heart may retain its insulin sensitivity in terms of insulin's ability to activate IRS1, PI3K ad Akt signaling, despite insulin resistance in other organs such as the liver and skeletal muscle. This hyperinsulinemia also accelerates adverse LV remodeling in pressure overload hypertrophy and genetic reduction of insulin signaling in cardiomyocytes limits hypertrophic remodeling and reduces apoptosis in pressure overload, thereby preserving LV function. Our recent studies reveal that hyperinsulinemia desensitizes ?R-mediated stimulation of cardiac contractility, which represents a novel mechanism linking insulin resistance, hyperinsulinemia and LV dysfunction. This proposal, will therefore focus on the hypothesis that hyperinsulinemia might attenuate LV contractility by directly impairing ?or ?-adrenergic (?) signaling. Specifically, activation of cardiomyocyte insulin receptors (IR) in hyperinsulinemic states, impairs ? signaling via two distinct mechanisms: (1) Increased ?R/Gi coupling that inhibits adenylyl cyclase and cAMP production, and (2) Increased expression of PDE4D that increases cAMP degradation. This multi PI proposal reflects an active collaboration by the laboratories of Evan Dale Abel (University of Iowa) and Yang Kevin Xiang (University of California -Davis). Our combined expertise in myocardial insulin signaling and myocardial adrenergic signaling will address this hypothesis in the following two specific aims. Aim 1 (Xiang). Will define the molecular mechanisms by which insulin impairs ? signaling in cardiomyocytes by testing the following hypotheses: Insulin signaling increases ?R/Gi coupling via a complex containing ?R, IR, IRS, and GRK2 that inhibits adenylyl cyclase-mediated cAMP generation. Insulin signaling enhances cardiac PDE4 levels via ?R-ERK dependent modulation of PDE4 transcription and protein turnover. Aim 2 (Abel). Will determine the physiological consequences of ?-IR interactions in hearts in vivo by testing the hypotheses that: Acute or chronic hyperinsulinemia will impair myocardial ? signaling and reduce contractility or inotropic reserve and that hyperinsulinemia in obesity, T2DM and heart failure will exacerbate cardiac dysfunction by impairing inotropic reserve. By using novel molecular biosensors to define subcellular adrenergic signaling domains in cardiomyocytes and a comprehensive array of mutant mouse models with perturbed IR or ? signaling, we will dissect the mechanism for IR-? crosstalk that limits myocardial contractility in insulin resistant states.